The carbostyril derivatives of formula (1) or salts thereof and the processes for the preparation thereof are disclosed in JP-63-20235-B and JP-55-35019-A. And it is known that the carbostyril derivatives (1) have platelet aggregation inhibition action, phosphodiesterase (PDE) inhibition action, antiulcer, hypotensive action and antiphlogistic action, and are useful as an antithrombotic agent, a drug for improving cerebral circulation, an antiinflammatory agent, an antiulcer drug, an antihypertensive drug, an antiasthmatic drug, a phosphodiesterase inhibitor, etc. A carbostyril derivative of the above formula (1), especially 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril (cilostazol) is on sale, which has an efficacy for improving various ischemic diseases such as ulcer, pain and coldness that are symptoms based on chronic arterial occlusion.
Carnitines are also called vitamin BT, which are biosynthesized from essential amino acids: lysine and methionine in liver/kidney. Carnitines can penetrate a cell membrane with comparative ease and thus they are distributed to each organ and also excreted to urine. Well known carnitines are L-carnitine, carnitine chloride, levocarnitine chloride, acetylcarnitine, etc. Especially, levocarnitine chloride is on sale (commercial name: L-Cartin tablets), which has an efficacy for improving levocarnitine deficiency in propionic academia or methylmalonic acidemia, and also it is indicated that levocarnitine chloride may be useful for improving circulatory failure in lower limbs. Further, L-carnitine is also known as a food material.
Occlusive peripheral arterial disease includes acute arterial occlusive disease, thromboangiitis obliterans, arteriosclerosis obliterans, lumbar spinal stenosis, intermittent claudication and the like.
Acute arterial occlusive disease is a disease that artery is rapidly occluded for some reasons, and the symptom thereof includes sudden pain, coldness, pallor, numbness, etc.
Thromboangiitis obliterans is vasculitis in peripheral artery of extremities, especially which often happens to feet, and it is known as Buerger's disease which is chronic arterial occlusion. In addition, thromboangiitis obliterans is designated as a specific rare disease by the Japan Ministry of Health and Welfare.
Arteriosclerosis obliterans is a disease that artery of extremities is arterio-sclerosed to become stenosis/occlusion and at last circulatory deficit.
Lumbar spinal stenosis is a disease that lumbar spinal canal is constricted for some reasons and nerve tissue therein is compressed.
Intermittent claudication is the most general symptom of peripheral arterial disease, which is caused by gradually narrowing artery of feet. The symptom includes pain, cramp, and muscular lassitude, which happens in regular intervals during movement. The pain ceases when taking a break and thus it gets possible to start walking again, however, the pain happens again when walking in the same distance as walking before. Intermittent claudication may often follow from acute arterial occlusive disease, thromboangiitis obliterans, arteriosclerosis obliterans, and lumbar spinal stenosis.
The cause of cerebrovascular accident is that any trouble happens to cerebral blood vessel (blood flow), and then the subsequent hemorrhage causes inflammation/exclusion or the subsequent ischemia causes brain tissue disorder. Cerebrovascular accident includes acute cerebral infarction, chronic cerebral infarction, transient ischemic attack, intracerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma, cerebrocortical dysfunction, cranial neuronal cell death, etc. And, cerebral infarction means that brain tissue is necrotized or nearly necrotized caused by occlusion/stenosis in artery and the subsequent ischemia.